Chronic High-fat Diet Research Articles

Effect of Sleeve Gastrectomy on Proprotein Convertase Subtilisin/Kexin Type 9 (Pcsk9) Content and Lipid Metabolism in the Blood Plasma and Liver of Obese Wistar Rats

Nowadays, obesity and its complications are heavy burdens to western civilization. Surgical procedures remain one of the available therapies for obesity and obesity-associated diseases treatment. Among them, sleeve gastrectomy is the most common bariatric procedure. Despite the well-established fact that sleeve gastrectomy results in significant weight loss, some of its other divergent effects still need to be established. To fulfill this knowledge gap, we examined whether sleeve gastrectomy affects lipid metabolism in the plasma and liver of obese rats. We demonstrated that chronic high-fat diet feeding led to an increment in the level of Proprotein Convertase Subtilisin/Kexin (PCSK)—a regulator of plasma cholesterol concentration—in the liver, which was decreased after the gastrectomy. Moreover, we noticed significant increases in both plasma and liver contents of free fatty acids, diacylgycerides and triacylglycerides in the obese animals, with their reduction after the bariatric surgery. In conclusion, we revealed, presumably for the first time, that sleeve gastrectomy affects lipid metabolism in the liver of obese rats.

Modulation of high fat diet-induced microbiome changes, but not behaviour, by minocycline

An emerging novel therapeutic agent for major depressive disorder, minocycline, has the potential to influence both gut microbiome and inflammatory status. The present study showed that chronic high fat diet feeding led to changes in both behaviour and the gut microbiome in male mice, without an overt inflammatory response. The diet-induced behavioural changes were characterised as increased immobility in the forced swim test and changes in locomotor activities in the open field test. Minocycline significantly altered the gut microbiome, rendering a community distinctly different to both untreated healthy and diet-affected states. In contrast, minocycline did not reverse high fat diet-induced changes in behaviour.

Abstract P179: Time Restricted Feeding Improves Blood Pressure and Heart Rate Rhythms as Well as Activation of NOS3 and AMP Kinase in Mice on a Chronic High Fat Diet

Irregular timing of food intake increases cardiometabolic disease and hypertension risk. A chronic high fat diet (HFD) leads to loss of endothelial function and reduced activation of endothelial NO synthase (NOS3). We hypothesized that restricting food availability to the active period in mice on HFD will restore the blood pressure rhythm and NOS3 activation. Mice (male 8-week old, C57BL/6J) were given normal diet (ND; 10% fat) or HFD (45% fat) for 20 weeks ad lib. During the final 2 weeks, food availability was limited to the active phase (restricted feed, RF) in half the HFD mice. Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured by telemetry. At the end of the study, 24 hr MAP, HR, and locomotor activity were similar in all groups. However, RF significantly increased the difference in MAP and HR between active and inactive periods in mice on HFD (MAP: ND: 16±0.7 mmHg, HFD: 15±0.8 mmHg, HFD+RF: 18±0.9 mmHg, n=6-8, p=0.01; HR: ND: 68±5.1 bpm, HFD: 69±6.5 bpm, HFD+RF: 113±7.9 bpm, n=6-8, p<0.01). The active-inactive difference in activity was similar in ND, HFD, and HFD+RF (p>0.05). At the end of the study, aorta (Ao) and renal vessels (RV) were isolated in the middle of the active period (ZT17). Western blotting revealed that diet or RF did not affect total NOS3, total Akt kinase (Akt), pAkt(S473), or total AMPK abundance in either vascular bed. pNOS3(S1177) abundance in Ao was improved by RF in HFD mice (ND: 8.5±4.7 rdu, HFD: 0.5±0.2 rdu, HFD+RF: 2.1±0.6 rdu, n=4, p=0.06). RF in HFD mice increased aortic pAMPK(T172) activation at ZT17 but not in renal vessels (Ao: ND: 0.2±0.1 rdu, HFD: 0.2±0.1 rdu, HFD+RF: 0.7±0.2 rdu, n=4-5, p=0.01; RV: ND: 0.8±0.2 rdu, HFD: 0.5±0.1 rdu, HFD+RF: 0.7±0.2 rdu, n=5-6, p=0.30). Plasma nitrite was significantly decreased in HFD and HFD+RF mice at ZT17 compared to ND mice (HFD: 0.6±0.04 μM; HFD+RF: 0.7±0.03 μM; ND: 1.4±0.3 μM; n=6, p=0.03). Our findings indicate that RF increases the differences in diurnal MAP and HR as well as increased activation of NOS3 and AMP kinase in mice on a chronic high fat diet. In conclusion, these results suggest that timing of food intake on a HFD improves MAP and HR rhythms possibly via increased activation of NOS3 and AMPK.

Abstract P3035: Role of T Cells in Sex Differences in Blood Pressure Elevation and Adipose Tissue Expansion Following Chronic High Fat Diet Feeding in Dahl Rats

Diets high in saturated fats are increasingly linked to the development of hypertension, yet the mechanisms by which high saturated fat diet (HFD) increases blood pressure remain unclear. Although young women are typically protected from hypertension relative to age-matched men, recent studies suggest that the cardiovascular protection in young women is compromised by chronic consumption of a HFD. We hypothesize that chronic HFD treatment causes a greater increase in blood pressure in females via sex-specific activation and recruitment of T cells and adipocyte expansion. Male and female Dahl rats (n=4-5) were placed on HFD at 8 wks of age. After 4 wks of HFD, blood pressure (BP) significantly increased in male and female Dahl rats to a comparable degree. Although BP continued to increase over the course of 10 wks of HFD treatment, female rats have a greater increases in BP (~40 mmHg increase in BP) after 10 weeks of HFD vs. males (~20 mmHg increase in BP). Fat pad weight and adipose tissue expansion increased in WT rats of both sexes following 10 wks of HFD treatment, yet females exhibited greater increases in fat pad weight and adipose tissue expansion vs. males. To determine whether T cells contributes to sex differences in BP elevation in Dahl rats fed HFD, we utilized Dahl rats lacking CD247 which encodes the T cell receptor CD3 chain that is required for T cell signaling. 10 wks of HF feeding did not change BP in either sex of Dahl CD247 KO rats. There were attenuated increases in fat pad weight and adipocyte expansion in Dahl CD247 KO rats and females exhibited more pronounced attenuations than males. Flow cytometric analysis revealed that HFD decreased Tregs and increased Th17 cells in both sexes of Dahl WT rats and females on HFD had the most pro-inflammatory T cell profile indicted by the Th17 cells:Tregs ratio. Our data suggest that greater adipocyte expansion with a HFD feeding in female Dahl rats vs. male might result in greater recruitment and activation of pro-inflammatory T cells and larger increases in BP.

Hydrogen sulfide potentiates the favorable metabolic effects of inorganic nitrite in type 2 diabetic rats

ObjectiveDecreased nitric oxide (NO) bioavailability and hydrogen sulfide (H2S) deficiency have been linked with the pathophysiology of type 2 diabetes (T2D). Restoration of NO levels by nitrite have been associated with favorable metabolic effects in T2D. Moreover, H2S can potentiate the effects of NO in the cardiovascular system. The aim of this study was to determine the effects of long-term co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on carbohydrate metabolism in type 2 diabetic rats. MethodsT2D was induced using chronic high fat diet (HFD) feeding combined with low dose streptozotocin (STZ) regimen. Rats were divided into 5 groups (N = 10/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite + NaSH. Nitrite (50 mg/L in drinking water) and NaSH (0.28 mg/kg, daily i. p. injection) were administered for 9 weeks. Fasting serum glucose, insulin, lipid profile, liver function tests, and oxidative stress indices were measured. Intraperitoneal glucose tolerance test (GTT) was performed at the end of the eighth week, and three days later, intraperitoneal pyruvate tolerance test (PTT) was done. Protein levels and mRNA expression of glucose transporter type 4 (GLUT4) in soleus muscle and epididymal adipose tissue as well as mRNA expression of H2S-producing enzymes in the liver, soleus muscle, and epididymal adipose tissue were measured at the end of the study. ResultsCompared to the controls, HFD and STZ treated rats developed metabolic dysfunction. Nitrite treatment improved carbohydrate metabolism, liver function, and oxidative stress indices whereas NaSH treatment per se had no significant effects. However, co-administration of NaSH and nitrite resulted in further improvement in serum insulin level, GTT, PTT, liver function, oxidative stress, protein level and mRNA expression of GLUT4, as well as mRNA expression of H2S-producing enzymes in diabetic rats. ConclusionLow dose of NaSH per se had no effect on carbohydrate metabolism while it potentiated the favorable metabolic effects of inorganic nitrite in type 2 diabetic rats. These favorable effects were associated with decreased oxidative stress and increased GLUT4 expression in insulin-sensitive tissues as well as improvement of liver function.

Prolonged high-fat-diet feeding promotes non-alcoholic fatty liver disease and alters gut microbiota in mice.

BACKGROUNDNon-alcoholic fatty liver disease (NAFLD) has become an epidemic largely due to the worldwide increase in obesity. While lifestyle modifications and pharmacotherapies have been used to alleviate NAFLD, successful treatment options are limited. One of the main barriers to finding safe and effective drugs for long-term use in NAFLD is the fast initiation and progression of disease in the available preclinical models. Therefore, we are in need of preclinical models that (1) mimic the human manifestation of NAFLD and (2) have a longer progression time to allow for the design of superior treatments.AIMTo characterize a model of prolonged high-fat diet (HFD) feeding for investigation of the long-term progression of NAFLD.METHODSIn this study, we utilized prolonged HFD feeding to examine NAFLD features in C57BL/6 male mice. We fed mice with a HFD (60% fat, 20% protein, and 20% carbohydrate) for 80 wk to promote obesity (Old-HFD group, n = 18). A low-fat diet (LFD) (14% fat, 32% protein, and 54% carbohydrate) was administered for the same duration to age-matched mice (Old-LFD group, n = 15). An additional group of mice was maintained on the LFD (Young-LFD, n = 20) for a shorter duration (6 wk) to distinguish between age-dependent and age-independent effects. Liver, colon, adipose tissue, and feces were collected for histological and molecular assessments.RESULTSProlonged HFD feeding led to obesity and insulin resistance. Histological analysis in the liver of HFD mice demonstrated steatosis, cell injury, portal and lobular inflammation and fibrosis. In addition, molecular analysis for markers of endoplasmic reticulum stress established that the liver tissue of HFD mice have increased phosphorylated Jnk and CHOP. Lastly, we evaluated the gut microbial composition of Old-LFD and Old-HFD. We observed that prolonged HFD feeding in mice increased the relative abundance of the Firmicutes phylum. At the genus level, we observed a significant increase in the abundance of Adercreutzia, Coprococcus, Dorea, and Ruminococcus and decreased relative abundance of Turicibacter and Anaeroplasma in HFD mice.CONCLUSIONOverall, these data suggest that chronic HFD consumption in mice can mimic pathophysiological and some microbial events observed in NAFLD patients.

Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus

BackgroundHypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3–6 months to induce chronic obesity.ResultsThe transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein.ConclusionsAltogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.

Journal Digest: Social Media; Opioid-Stimulant Deaths; Antidepressant Effects; Testosterone; Menstruation

Journal Digest: Social Media; Opioid-Stimulant Deaths; Antidepressant Effects; Testosterone; Menstruation

Zoledronic acid prevents the hepatic changes associated with high fat diet in rats; the potential role of mevalonic acid pathway in nonalcoholic steatohepatitis

The role of hepatic free cholesterol (FC) in nonalcoholic steatohepatitis (NASH) is raised up and the intervention with cholesterol synthesis will be a potential therapeutic target. This study investigated the hepatoprotective effect of mevalonic acid pathway inhibition by Zoledronic acid (ZA) on the hepatic changes associated with high fat diet (HFD) in rats.Thirty two male Wistar rats were used. They were divided into 2 groups: (I) control naïve (II) NASH: induced by HFD for 12 weeks, this group is subdivided into (A) NASH untreated (B)NASH + ZA (50ug/kg/week) i.p. for 12 weeks (C) NASH + ZA (100μg/kg/week) i.p. for 12 weeks. Portal pressure (PP), liver enzymes AST and ALT, serum glucose, lipid profile, hepatic levels of tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), FC and triglyceride (TG), histopathological changes and expression of both hepatic alpha smooth muscle actin (α-SMA) and Caspase-3 were measured. ZA significantly prevented portal hypertension, worsening in liver function, and dyslipidemia. The hepatic levels of TNF-α, VEGF, FC and TG were significantly decreased in comparison to NASH untreated group. ZA hindered the histopathological changes induced by HFD. ZA inhibited the expression of hepatic α-SMA and Caspase-3 with significant difference favor the high dose intervention. ZA in a dose related manner prevents the hepatic pathological effects of chronic HFD ingestion in rats. This may be largely mediated by its ability to reduce TNF-α and hepatic FC.

Chronic high-fat diet decreased detrusor mitochondrial respiration and increased nerve-mediated contractions.

To assess the impact of chronic high-fat diet (HFD) on behavioral voiding patterns, detrusor contractility, and smooth muscle mitochondrial function in male mice. Male C57BL/6J mice (6 weeks) were fed a control or HFD for 20 weeks. Bladder function was assessed by void spot assays. Bladders were collected and detrusor contractility to carbachol (10-9 -10-5 M), and electrical field stimulation (EFS, 0.5-32 Hz) in the presence and absence of atropine was measured. Homogenized detrusor samples were placed in oxygraphs to assess the rate of oxygen consumption of the mitochondria within the detrusor in the presence of different substrates. Mitochondrial hydrogen peroxide (H2 O2 ) emission was measured fluorometrically. Detrusor citrate synthase activity was measured via enzyme activity kit and Western blots assessed the electron transport chain (ETC) protein content. HFD significantly increased body weight, adiposity, and blood glucose levels. HFD mice demonstrated increased voiding frequency and increased EFS-induced detrusor contractility. There were no changes in detrusor relaxation or cholinergic-medicated contraction. Mitochondrial respiration was decreased with HFD and H2 O 2 emission was increased. The relative amount of mitochondria in the detrusor was similar between groups. However, ETC complexes V and III were increased following HFD. Chronic HFD increased adiposity, lead to more frequent voiding, and enhanced EFS-mediated detrusor contractions. Mitochondrial respiration was decreased and H2 O 2 emission increased following HFD. Further research is required to determine if alterations in mitochondrial function could play a role in the development of HFD-induced bladder dysfunction.

A Brain-Melanocortin-Vagus Axis Mediates Adipose Tissue Expansion Independently of Energy Intake

SUMMARYThe melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing sympathetic nervous system input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here, we demonstrate that reduction of brain-melanocortin signaling actively promotes fat mass gain by activating the lipogenic program and adipocyte and endothelial cell proliferation in white fat depots independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. Those vagally regulated obesogenic signals also contribute to the fat mass gain following chronic high-fat diet feeding. These data reveal a physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity.

SUN-099 Fibro-adipogenic Remodeling Of The Diaphragm In Obesity-associated Respiratory Dysfunction

Respiratory dysfunction is a common complication of obesity, conferring cardiovascular morbidity, increased mortality and often necessitating mechanical ventilatory support. While impaired lung expansion in the setting of increased adipose mass and reduced central response to hypercapnia have been implicated as pathophysiological drivers, the impact of obesity on respiratory muscles--in particular, the diaphragm--has not been investigated in detail. In this study, we demonstrate that chronic high-fat diet (HFD)-feeding impairs diaphragm muscle function, as assessed in vivo by ultrasonography and ex vivo by measurement of contractile force. During a HFD time course, progressive adipose tissue expansion and collagen deposition within the diaphragm parallel contractile deficits. Moreover, intra-diaphragmatic fibro-adipogenic progenitors (FAPs) proliferate with long-term HFD-feeding while giving rise to adipocytes and type I collagen-depositing fibroblasts. Thrombospondin-1 (THBS1), a circulating adipokine, increases with obesity and induces FAP proliferation. These findings suggest a novel role for FAP-mediated fibro-adipogenic diaphragm remodeling in obesity-associated respiratory dysfunction.

The Gut Microbiome on a Periodized Low-Protein Diet Is Associated With Improved Metabolic Health.

A periodized (14 days on/14 days off) 5% low protein-high carbohydrate (pLPHC) diet protects against weight gain, improves glucose tolerance in mice and interacts with concurrent voluntary activity wheel training on several parameters including weight maintenance and liver FGF21 secretion. The gut microbiome (GM) responds to both diet and exercise and may influence host metabolism. This study compared the cecal GM after a 13.5-week intervention study in mice on a variety of dietary interventions ± concurrent voluntary exercise training in activity wheels. The diets included chronic chow diet, LPHC diet, 40 E% high protein-low carbohydrate (HPLC) diet, an obesigenic chronic high-fat diet (HFD) and the pLPHC diet. Our hypothesis was that the GM changes with pLPHC diet would generally reflect the improved metabolic health of the host and interact with concurrent exercise training. The GM analyses revealed greater abundance phylum Bacteroidetes and the genus Akkermansia on chronic and periodized LPHC and higher abundance of Oscillospira and Oscillibacter on HFD. The differences in diet-induced GM correlated strongly with the differences in a range of host metabolic health-measures. In contrast, no significant effect of concurrent exercise training was observed. In conclusion, pLPHC diet elicits substantial changes in the GM. In contrast, only subtle and non-significant effects of concurrent activity wheel exercise were observed. The pLPHC-associated microbiome may contribute to the healthier host phenotype observed in these mice.

Restricting food availability to the active period restores rhythmic activation of aortic NOS3 in high fat diet fed mice

Timing of food intake increases the risk for cardiometabolic disease. A chronic high fat diet (HFD) leads to endothelial dysfunction with loss of nitric oxide (NO) signaling in mice. Both endothelial function and vascular resistance display circadian variation with endothelial‐dependent relaxation and NO signaling peaking during the active period, while vascular resistance peaks shortly after waking. We hypothesized that HFD leads to a loss of circadian rhythm in endothelial NO synthase (NOS3) activation that is restored by restricting food availability to the active period. Mice (male 8‐week old, C57BL/6J) were given normal diet (ND; 10% fat) or HFD (45% fat) for 20 weeks ad libitum. Restricted feeding (RF; food availability only during the active phase) was enforced in half the mice during the final 2 weeks of feeding. Aortae were harvested at 4‐hour intervals over a 24‐hour period (ZT0 at 7AM; ZT12 at 7PM). NOS3 (total and phosphorylation at serine 1177 (pNOS3(S1177)) was assessed by Western blotting. NOS3 expression was unchanged with time in all 4 groups. In mice on ad libitum ND, pNOS3(S1117) expression displayed a diurnal variation with peak expression at ZT17. HFD mice displayed a significantly blunted amplitude and an earlier acrophase of the diurnal rhythm in pNOS3(S1117) expression by cosinor analysis (amplitude: HFD: 1.4±0.4 rdu; ND: 4.8±0.6 rdu, n=3, p=0.01; acrophase: HFD: 10.3±1.6 hrs, ND: 15.7±1.4 hrs, n=3, p=0.06). RF with HFD restored the acrophase of the pNOS3(S1177) rhythm (HFD: 10.3±1.6 rdu; HFD+RF: 16.4±1.4 rdu, n=3, p=0.04). To further examine the mechanism of NOS3 activation, we determined the expression of AMP kinase (AMPK), Akt kinase (Akt), and phosphorylation sites on each kinase at ZT5 and ZT17. Interestingly, RF in HFD mice significantly increased pAMPK(T172) abundance at ZT17 (n=4–5, p=0.02) compared to ad libitum HFD mice. Expression of AMPK, Akt, and Akt phosphorylation sites were unaffected by RF on ND or HFD. We further examined the 24 hour mean arterial pressure (MAP), heart rate (HR), and locomotor activity by telemetry. MAP was similar in all 4 groups (n=5–6, ND: 113±1 m Hg; ND+RF: 109±4 mmHg; HFD: 118±3 mmHg; HFD+RF: 114±2 mmHg). HR was increased with HFD and reduced in mice exposed to HFD+RF similar to ND mice (n=5–6, p<0.05). Locomotor activity was significantly decreased in HFD and HFD+RF mice compared to ND (n=5–6, p<0.05). In summary, aortic NOS3 activation displays a rhythm peaking during the active period at ZT17. HFD depresses the rhythm of aortic NOS3 activation, while RF restores the rhythm with an associated activation of AMP kinase at ZT17. We propose that time restricted feeding may lower the incidence of vascular disease through maintenance of rhythmic vascular NOS3 activation.Support or Funding InformationSupported by T32 DK007545 to PP, an AHA pre‐doctoral fellowship (18PRE33990345) to DZ, P01 HL069999 to JSP and DMP, and P01 HL136267 to JSP, EWI, and DMP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic high fat diet lowers male detrusor mitochondrial fatty acid oxidation while females are protected

IntroductionObesity increases the prevalence of bladder dysfunction in both males and females. The bladder's mucosal and detrusor smooth muscle layers are involved in bladder signaling and contraction, respectively. The underlying causes of obesity‐induced bladder dysfunction in males and females are poorly understood. Mitochondrial dysfunction is common in the heart, liver and skeletal muscle with high fat diet (HFD). This study will characterize sex differences in mitochondrial respiration in bladder mucosal and detrusor layers. Additionally, we will determine the impact of long‐term HFD on bladder mitochondrial respiration in male and female mice.MethodsMale and female mice (n=7/group, 20–24 wks) were used to assess bladder mitochondrial sex differences. A second group of male and female mice (10 wks, n=5–7/group) were fed a control (10% kcal fat) or HFD (45% kcal fat) for 24 weeks. Bladders were collected, weighed and separated into mucosal and detrusor layers. Tissues were cut into strips, permeabilized, and placed in an OROBOROS Oxygraphy‐2K to measure respiration using a modified version of the creatine kinase energetic clamp. Substrates (pyruvate/malate, glutamate, L‐octanoylcarnitine/malate, or succinate/rotenone) were added followed by increasing concentrations of phosphocreatine to allow for substrate‐specific bioenergetic analyses across a physiological span of ATP free energies. Respiratory conductance was calculated for each substrate based on the rate of change in respiration for a given increase in ATP free energy.ResultsBladder respiration and respiratory conductance in the presence of L‐octanoylcarnitine/malate in mucosal and detrusor tissue was significantly decreased in males (p<0.05). Respiration and respiratory conductance remained unchanged between sexes in the presence of pyruvate/malate, glutamate, and succinate/rotenone. Chronic HFD increased body weight and decreased the bladder to body weight ratio in both sexes (p<0.05). In HFD males, mucosal respiration and respiratory conductance were decreased in the presence of L‐octanoylcarnitine/malate (p<0.05). In contrast, pyruvate/malate, glutamate, and succinate/rotenone did not change HFD male respiration and respiratory conductance. In HFD females, respiration and respiratory conductance were unchanged in presence of pyruvate/malate, glutamate, and L‐octanoylcarnitine/malate. However, HFD female mucosal layer had decreased respiration with succinate/rotenone but no change in respiratory conductance.ConclusionsMale mice have lower baseline fatty acid metabolism within the bladder's detrusor smooth muscle layer compared to females. With chronic HFD, male fatty acid metabolism within the mucosal and detrusor muscle layers is further lowered whereas female mice are protected. Ongoing studies will determine if excess lipids accumulate within the bladder and if we can rescue fatty acid metabolism with co‐factors such as L‐carnitine or acetyl‐CoA. Understanding bladder metabolic and bioenergetic sex differences will help to create more effective treatments for bladder dysfunctionSupport or Funding InformationNIDDK DiaComp, ECU SBRP, APS UGSRFThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fluoxetine Ameliorates the Depressive‐Like Behaviors and Metabolic Abnormalities Induced by Chronic High‐Fat Diet

Major depressive disorder (MDD) is one of the most common psychiatric disorders, and frequently co‐occurs with multiple comorbidities, especially Type 2 diabetes mellitus. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used class of antidepressants. This study aimed to investigate the effects of fluoxetine (Prozac®), a SSRIs, on metabolic abnormalities induced by chronic high‐fat diet (HDF). Male HDF‐induced insulin resistance mice were administrated with fluoxetine (10 mg/kg and 20 mg/kg) by intraperitoneal injection for four weeks. The behavioral tests showed that fluoxetine significantly reversed the depressive‐like behaviors induced by chronic HDF, including the reduced sucrose preference and increased immobility time in the forced swimming test and tail suspension test. Moreover, fluoxetine also reduced serum level of glucose and improved blood lipid profiles in HFD‐treated mice. Furthermore, fluoxetine improved impaired glucose tolerance and insulin sensitivity. Our results indicated that fluoxetine could ameliorate depressive‐like behaviors and metabolic abnormalities induced by chronic HFD, which suggested that the multiple effects of fluoxetine could be beneficial for patients with depression and/or metabolic syndrome.Support or Funding InformationThis work is supported by Ministry of Science and Technology, Taiwan (MOST 106‐2320‐B‐006‐058‐MY3)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges.

Tissue-resident macrophages are the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophages (ATMs) change during metabolic stress and are thought to contribute to metabolic syndrome. Here, we studied ATM subpopulations in steady state and in response to nutritional and infectious challenges. We found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying very high endocytic capacity. We refer to these cells as vasculature-associated ATMs (VAMs). Chronic high-fat diet (HFD) results in the accumulation of a monocyte-derived CD11c+CD64+ double-positive (DP) macrophage eWAT population with a predominant anti-inflammatory/detoxifying gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that ATM populations dynamically adapt to metabolic stress and inflammation, suggesting an important role for these cells in maintaining tissue homeostasis.

Chronic High-Fat Diet Exacerbates Sexually Dimorphic Pomctm1/tm1 Mouse Obesity.

Mice with a targeted mutation in the pro-opiomelanocortin (Pomc) gene (Pomctm1/tm1 mice) are unable to synthesize desacetyl-α-MSH and α-MSH and they develop obesity when fed chow diet. In this study, we hypothesized that a chronic high-fat (HF) diet exacerbates Pomctm1/tm1 mouse obesity. Male and female Pomcwt/wt and Pomctm1/tm1 mice were fed low-fat (LF) (10 kcal percent fat) or HF (45 kcal percent fat) diets from weaning for 23 weeks. We show that Pomctm1/tm1 mouse obesity is sexually dimorphic and exacerbated by an HF diet. Male Pomctm1/tm1 mice develop obesity because they are hyperphagic compared with Pomcwt/wt mice when fed an LF or HF diet. Female Pomctm1/tm1 mice develop obesity when feeding on an LF or HF diet because they exhibit signs of reduced energy expenditure (no change in feed efficiency; body weight gained exceeding energy intake) compared with Pomcwt/wt mice. A chronic HF diet exacerbates male Pomctm1/tm1 and Pomcwt/wt mouse obesity, and the increased energy intake fully accounts for increased weight gain. In contrast, female Pomcwt/wt mice are protected from chronic HF diet–induced obesity because they reduce the amount of HF diet eaten, and they appear to increase their energy expenditure (no change in feed efficiency but energy intake exceeding body weight gained). A chronic HF diet exacerbates female Pomctm1/tm1 mouse obesity due to impaired ability to reduce the amount of HF diet eaten and apparent impaired HF diet–induced adaptive thermogenesis. Our data show that desacetyl-α-MSH and α-MSH are required for sexually dimorphic HF diet–induced C57BL/6J obesity. In conclusion, desacetyl-α-MSH and α-MSH play salutary roles in sexually dimorphic melanocortin obesity and sexually dimorphic HF diet–induced C57BL/6J obesity.

Chronic Adherence to a Ketogenic Diet Modifies Iron Metabolism in Elite Athletes.

The short-term restriction of carbohydrate (CHO) can potentially influence iron regulation via modification of postexercise interleukin-6 (IL-6) and hepcidin levels. This study examined the effect of a chronic ketogenic low-CHO high-fat (LCHF) diet on iron status and iron-regulatory markers in elite athletes. International-level race walkers (n = 50) were allocated to one of three dietary interventions: (i) a high-CHO diet (n = 16), (ii) a periodized CHO availability (n = 17), or (iii) an LCHF diet (n = 17) while completing a periodized training program for 3 wk. A 19- to 25-km race walking test protocol was completed at baseline and after adaptation, and changes in serum ferritin, IL-6, and hepcidin concentrations were measured. Results from high-CHO and periodized CHO were combined into one group (CHO; n = 33) for analysis. The decrease in serum ferritin across the intervention period was substantially greater in the CHO group (37%) compared with the LCHF (23%) group (P = 0.021). After dietary intervention, the postexercise increase in IL-6 was greater in LCHF (13.6-fold increase; 95% confidence interval [CI] = 7.1-21.4) than athletes adhering to a CHO-rich diet (7.6-fold increase; 95% CI = 5.5-10.2; P = 0.033). Although no significant differences occurred between diets, CI values indicate that 3 h postexercise hepcidin concentrations were lower after dietary intervention compared with baseline in CHO (β = -4.3; 95% CI = -6.6 to -2.0), with no differences evident in LCHF. Athletes who adhered to a CHO-rich diet experienced favorable changes to the postexercise IL-6 and hepcidin response, relative to the LCHF group. Lower serum ferritin after 3 wk of additional dietary CHO might reflect a larger more adaptive hematological response to training.

Pentoxifylline ameliorates chronic stress/high-fat diet-induced vascular wall disease: the role of circulating endothelial progenitor cells.

Depression and cardiovascular disease (CVD) are two faces of one coin. A pro-inflammatory state was previously suggested in the pathology of both diseases. We investigated the effect of chronic administration (2weeks) of imipramine (20mg/kg/day) and pentoxifylline (50mg/kg/day) on behavioral, aortic histological abnormalities, and level of circulating endothelial progenitor cells (CEPCs) in peripheral blood of male Wistar rats exposed to chronic mild stress (CMS) and high-fat diet. Exposure to CMS and high-fat diet induced a depressive-like behavior alongside aortic immunohistochemical changes associated with an increase in aortic TNF-α level. Markers of CEPCs, VEGFR-2 and CD133, were significantly disturbed in aortic sections, as compared to control animals and those exposed to CMS while fed high-fat diet, although flowcytometric analysis did not show any significant changes in the level of CEPCs in peripheral blood. Chronic pentoxifylline treatment was more effective in ameliorating the histological changes and endothelial damage compared to imipramine. Pro-inflammatory cytokines-induced disturbances in CEPCs could constitute a plausible link between depression and atherosclerotic cardiovascular disease. Current antidepressants reduce symptoms of depression without tackling the underlying link between it and cardiovascular disease. Targeting pro-inflammatory cytokines might open a new therapeutic approach to alleviate depression and reduce the risk of mortality from cardiovascular disease.